Heterocyclic nitrogen compounds containing sulfonyl fluoride groups and method of producing same



3,074,9at8 HETERUCYCLEC NETRGGEN CQMPQUNDS CON- TAINING SULFGNYL FLUURHDE GRQUPS AND METHQD (3F PRODUCHNG AME Alden G. Eearnan, Tempe, Ariz. 9 D fi i l l d M y 1, 1%? S QP 12. Claims- C l. ass- 254 My invention relates to purinesulfonyl fluorides, and to methods for preparing same, which methods are also applicable tothe production of other heterocyclic nitrogen c mpound con s ny flu ide o p The principal object of my invention is the provision of new compositions of matter comprising purinesulfonyl fluorides which are active in the treatment of certain animal tumors, but which also serve as useful chemical intermediates as in the synthesis of purinesulfonamides.

Another object is the provision of an improved method for introducing sulfonyl fluoride groups into heterocyclic nitrogen systems.

The purinesulfonyl fluorides of my invention may be represented by the formula and in which X is a hydrogen, chloride, hydroxy or amino radical.

These new compounds are prepared from mercaptopurines and substituted mercaptopurines prepared by known processes. In carrying out the method, the mercaptopurine is added to a compatible aqueous liquid maintained at or near zero degrees .centigrade by suitable means such as a brine bath, which liquid provides an active source of fluoride ions and a bufler; and an oxidizing agent such as halogen is introduced into the mixture while it is constantly stirred until reaction has gone to completion. The compatible liquid is preferably a mixture of a relatively low molecular weight monohydric alcohol such as methanol and an aqueous solution of an acid fluoride salt or hydrofluoric acid in which a fluoride salt has been dissolved. After completion of the reaction, the purified product is found to be a purinesulfonyl fluoride in which a merc apto radical has been replaced by SO F. This process may also be employed advantageously to produce other heterocyclic nitrogen compounds containing a sulfonyl fluoride group or groups,

3,074,948 Patented Jan. 22, 1963 2 5 .91 1 t tute p idines, subs itu e p rim dines a the like. I

While various metal salts of fluoride may be used, I found that potassium fluoride, because of its greater solubility under the conditions of the reaction, is preferred as contrasted with such metal salts as calcium or sodium fluorine. Also, while other halogens can be employed as oxidizing agents, chlorine is preferred because of its demonstrated activity and stability. These illustrative examples, therefore, should not be interpretedas'limiting the scope of the invention.

' The starting rnercapto heterocyclic compound containing nitrogen maybe made by various methods disclosed in the chemicalliterature. Such starting materials may be represented by the formula where X, Y- and Z are selected from the class consisting of hydrogen, halogen, hydroxy, amino and rnercapto radicals, and in which at least one of X, Y and is a mercapto radical.

The tollow ng examp es a e i ust ati e, b th of t e m ho and the pu mesu s onyl fl ori es producible by method.

. EX PL 1 fu ia rfi-S lfony l gride A mixture is first prepared To the above, 20 grams of fi-mercaptopurine are added with stirring, and the flask set in a brine bath and cooled to -B C. Chlorine is then bubbled slowly through the mixture as stirring continues and reaction is allowed to proceed for about two hours. When the chlorine is introduced, the yellow mercapto purine color disappears, and the reaction mixture takes on a whitish pasty appearance. Completion of the reaction is indicated after about two hours by a slight drop in the temperature of thereactio'n mixture. During the reaction the condition of the reaction may also be checked by temporarily dis continuing'flow of chlorine and using ordinary laboratory pH pap a a check 9 comple ion o th rea tion the pl-l paper turns white, but when the reaction is pro.- s di n rm t e PH Pap u s r and not bleached by the mixture until the reaction has been icornr e edi I When the reaction has gone to completion, the contents of the flaskare poured over crushed ice .while stirring the mixture 'to maintain a temperature well below 0 C. While still holding a temperature below 0 vC. .by introduc n ddi a 'is as q i ed worme r a i m hydroxide solution isadded with stirring until the mass shows a pH of 3. The product is filtered, washed with ice water and then acetone'dissolved in hot ethanol or methanol and .the solution cooled to crystallize the end product out of solution. yield is about ,8 to 10 ams s n rin es ion (flu i The product of the above reaction is a white crystalline ,solid which decomposes at about 235 0. without melting. It is soluble in acetone, ethanol and methanol. When heated n boi i Wa e i decom o s t fi-h d ryp ri t ha a d s nct ve v. lt a q i abs rpt on s ect um Kt max-=2 me 8.5 in p uti n a sqha 3 EXAMPLE 2 6-Chloropurine-Z-Sulfonyl Fluoride Ten grams of 2,6-dimercaptopurine were added with stirring to a mixture of The'mixture was maintained at l0 C. for 1 /2. hours while constantly stirred and with C1 continuously bubbled through the mixture. At the end of the reaction as shown by bleaching of pH paper, the entire reaction mixture was mixed with crushed ice, the pH adjusted to 3 with KOH, the precipitate washed with ice water and dried. The precipitate was then dissolved in 200 ml. of acetone at room temperature, filtered to remove insoluble material, and the acetone evaporated to dryness. The product was thenrecrystallized from methanol. About 5 grams of a pale yellow crystalline solid was obtained with a melting point of 202-205 C. It has a distinctive ultraviolet absorption spectrum (A max. 271 m e=8560) in methanol..

EXAMPLE -3 o-Hydroxypurine-Z-Sulfonyl Fluoride Ten grams of 2-mercapto-6-hydroxypurine were added to a flask containing the following:

Methanol ml 30 Aqueous .HF (49%) ml 60 Potassium fluoride (KPXH O) g 55 The mixture was held within about 5 C. of zero in a brine bath, constantly stirred, and chlorine gas bubbled slowly through it. At the end of the reaction period which occurred in about one and one half hours, 10.7 grams of a reaction product were obtained by pouring the reaction mixture on excessice, adjusting the pH to 4 by KOH addition and filtering oh? and drying the solid. The new product was a white powdery solid which analytical tests showed to be 6-hydroxypurine-2-sulfonyl fluoride. It showed a distinctive ultraviolet absorption spectrum in water (A max. 263 m e=87l0 at pH 11).

EXAMPLE 4 6-Aminopurine-Z-Sulfbnyl Fluoride Five grams of Z-mercapto-6-aminopurine were added to Methanol ml 13 Hydrofluororic acid (49% HF) ml 33 KF.2H O g 28 and the mixture cooled and held at .S C. while stirred and with C1 bubbling through it. Reaction time was 1% hours. The entire reaction mass was poured on crushed ice, the solid filtered, washed with ice water and dried. A yield of 4.5 grams of a white powdery solid was obtained. In water at pH 11 it showed a distinctive ultraviolet absorption spectrum (7t max. 281 mp, e=8400).

I claim:

1. The method of producing a sulfonyl fluoride-substituted heterocyclic compound, said heterocyclic moiety selected from the group consisting of purine, pyridine and pyrimidine, which comprises mixing a mercapto derivative of said heterocyclic compound at a relatively low temperature with a mixture containing a relatively low molecular weight alcohol and a buffered aqueous solution containing a fluoride ion and continuously delivering a halogen to the reaction mixture, to oxidize the sulfur of the mercapto group and convert such mercapto group into a sulfonyl fluoride group.

2. The method of producing a purinesulfonyl fluoride which comprises mixing together a mercaptopurine, a relatively low molecular alcohol and a bufiered aqueous solution containing a fluoride ion, holding the mixture at or near 0 C. and continuously introducing a halogen to the mixture until a reaction has been completed in which a sulfonyl fluoride group replaces the mercapto group of the mercaptopurine.

3. The method of producing a purine derivative of the class consisting of purinemonosulfonyl fluoride, purinedisultonyl fluoride and purinetrisulfonyl fluoride which comprises reacting a mercaptopurine of the class consisting of monomercaptopurine, dimercaptopurine and trirnercaptopurine with a fluoride radical at about 0 C. in the presence of chlorine as an oxidizing agent to convert at least one mercapto group to a sulfonyl fluoride group.

4. The method of producing a purine derivative containing at least one sulfonyl fluoride group in at least one of the positions 2, 6 and 8 on the purine ring, which comprises forming a liquid mixture containing methanol and an aqueous solution of a metal fluoride salt and hydrofluoric acid, introducing into the mixture a compound having the chemical formula Y i N in which X, Y and Z are selected from a class consisting of H, Cl, NH and SH radicals, at least one of which is an SH radical, cooling the mixture, and continuously introducing halogen as an oxidizing agent, and continuing the reaction until at least one SH radical is converted to -SO F.

5. The method of producing a purine derivative containing at least one sulfonyl fluoride group in at least one of the positions 2, 6 and 8 on the purine ring, which comprises forming a liquid mixture containing methanol and an aqueous solution of KHF introdu-cing'into the mixture a compound having the chemical formula flit Y H i N 1 t X N,-N

in which X, Y and Z are selected from a class consisting of H, Cl, OH, NH and SO F radicals, and in which at least one of such X, Y and Z is an S0 radical.

7. A chemical compound having the formula in which Y'is selected from the class consisting of a hy-@ drogen chloride, hydroxy and amino radical. 4

8. A chemical compound having the formula 10-. 6-chloropurine-2-sulfonyl fluoride. 11. G-aminopurine-Z-sulfonyl fluoride.

i 12. '6-hydroxypur1ne-2-sulfonyl fluoride. W m 5 References Cited in the file of this patent X-kN Giner-Sorolla: Jour. Amer. Chem. 300., vol. 80, pages 3932-3937 (1958). in which X is selected from the class consisting of a hy- Giner-Sorolla: Jour. Amer. Chem. 800., vol. 80, pages drogen, chloride, hydroxy and amino radical. 57445748 (1958).

9. Purine-6-sulfony1 fluoride. 

6. A CHEMICAL COMPOUND HAVING THE FORMULA 